Crystallization enantiomer separation

Resolution methods using nonopticaHy active agents are also used by taking advantage of the fact that certain benzoic acid derivatives of (A)-menthol can be inoculated with crystals of one enantiomer to induce immediate crystallization of that enantiomer. Although repeated crystallizations and separations must be done, the technique has been successhil for (—)-mentho1 (157). 

The first resolution of an octahedral complex into its enantiomers was achieved in 1911 by A. Werner, who got the Nobel Prize in 1913, with the complex [Co(ethylenediamine)(Cl)(NH3)] [10]. Obviously, resolution is to be considered only in the case of kinetically inert complexes whose enantiomers do not racemize quickly after separation. This is a very important remark since, as noted above, the interesting complexes are those containing exchangeable sites required for catalytic activity and thus more sensitive to racemization. We will not discuss here the very rare cases of spontaneous resolution during which a racemic mixture of complexes forms a conglomerate (the A and A enantiomers crystallize in separate crystals) [11,12]. 

Conglomerate crystallization in the above case indicates that the inclusion approach may be further extended into the realm of the salt-type associates. Such an attempt is especially interesting due to the obvious role in enantiomer separation which relies heavily on the solubility difference of the enantiomeric salts under certain circumstances 137). 

In a series of papers, cinchona alkaloid selectors were in the focus of preparative enantiomer separation methodologies including crystallization [57], countercurrent... 

In simple experiments, particulate silica-supported CSPs having various cin-chonan carbamate selectors immobilized to the surface were employed in an enantioselective liquid-solid batch extraction process for the enantioselective enrichment of the weak binding enantiomer of amino acid derivatives in the liquid phase (methanol-0.1M ammonium acetate buffer pH 6) and the stronger binding enantiomer in the solid phase [64]. For example, when a CSP with the 6>-9-(tcrt-butylcarbamoyl)-6 -neopentoxy-cinchonidine selector was employed at an about 10-fold molar excess as related to the DNB-Leu selectand which was dissolved as a racemate in the liquid phase specified earlier, an enantiomeric excess of 89% could be measured in the supernatant after a single extraction step (i.e., a single equilibration step). This corresponds to an enantioselectivity factor of 17.7 (a-value in HPLC amounted to 31.7). Such a batch extraction method could serve as enrichment technique in hybrid processes such as in combination with, for example, crystallization. In the presented study, it was however used for screening of the enantiomer separation power of a series of CSPs. 

Through luck, in 1848, Louis Pasteur was able to separate or resolve racemic tartaric acid into its (+) and (—) forms by crystallization. Two enantiomers of the sodium ammonium salt of tartaric acid give rise to two distinctly different types of chiral crystal that can then be separated easily. However, only a very few organic compounds crystallize into separate crystals (of two enantiomeric forms) that are visibly chiral as are the crystals of the sodium ammonium salt of tartaric acid. Therefore, Pasteur s method of separation of enantiomers is not generally applicable to the separation of enantiomers. 

Jeong HS, Tanaka S, Yoon DK, Choi S-W, Kim YH, Kawauchi S, Araoka F, Takezoe H, Jung H-T (2009) Spontaneous chirality induction and enantiomer separation in liquid crystals composed of achiral rod-shaped 4-arylbenzoate esters. J Am Chem Soc 131 15055-15060... 

Another case of major enantiomer separation occurs when helical tubuland diols (Section 3.2.1) are crystallised with small phenol molecules and intimately hydrogen bonded co-crystals are produced. A typical example is (11 ) ( p-chloro-phenol) [33], The major supramolecular synthon is H-0 H-0 H-0 hydrogen bonding with eclipsed stacks of the participating molecules surrounding a pseudo-threefold screw axis (Figure 13). This chiral motif involves molecules of p-chloroplienol and only one of the enantiomers of 11. 

This book illustrates the recent aspects of amplification of chirality by asymmetric auto catalysis and by forming helical structures. The first four chapters summarize experimental asymmetric autocatalysis with amplification of enan-tiopurity, the mechanism of asymmetric autocatalysis examined by NMR and calculation, the computer simulation models of the reaction mechanism of asymmetric auto catalysis, and the theoretical models of amplification of chirality. The last chapter deals with the amplification of chirality by the formation of helical structures. However, the amplification of enantiopurity in non-auto catalytic asymmetric reaction and the amplification by enantiomer separation involving crystallization or sublimation are beyond the scope of this book. 

In 1848, Louis Pasteur noticed that a salt of racemic ( )-tartaric acid crystallizes into mirror-image crystals. Using a microscope and a pair of tweezers, he physically separated the enantiomeric crystals. He found that solutions made from the left-handed crystals rotate polarized light in one direction and solutions made from the right-handed crystals rotate polarized light in the opposite direction. Pasteur had accomplished the first artificial resolution of enantiomers. Unfortunately, few racemic compounds crystallize as separate enantiomers, and other methods of separation are required. 

The first method of enantiomeric separation by direct crystallization is the mechanical technique use by Pasteur, where he separated the enan-tiomorphic crystals that were simultaneously formed while the residual mother liquor remained racemic. Enantiomer separation by this particular method can be extremely time consuming, and not possible to perform unless the crystals form with recognizable chiral features (such as well-defined hemihedral faces). Nevertheless, this procedure can be a useful means to obtain the first seed crystals required for a scale-up of a direct crystallization resolution process. When a particular system has been shown to be a conglomerate, and the crystals are not sufficiently distinct so as to be separated, polarimetry or circular dichroism spectroscopy can often be used to establish the chirality of the enantiomeric solids. 

Even a few seed crystals, mechanically separated, can be used to produce larger quantities of resolved enantiomerically pure material. A second method of resolution by direct crystallization involves the localized crystallization of each enantiomer from a racemic, supersaturated solution. With the crystallizing solution within the metastable zone, oppositely handed enantiomerically pure seed crystals of the compound are placed in geographically distant locations in the crystallization vessel. These serve as nuclei for the further crystallization of the like enantiomer, and enantiomerically resolved product grows in the seeded locations. 

Enantiomeric ( )-(+)- and (R)-(-)-BNP acids are useful resolving agents, which give well crystallized, easily separated salts with a variety of amines. They have been used In the preparation of the enantiomers of... 

Resolutions of the racemates of helicenes have been carried out in different ways Helicenes, which often spontaneously crystallize as conglomerates, have been successfully separated into the enantiomers by Pasteurs mechanical method. Enantiomer separation using the diastereomeric salts prepared from 7-triphenylphosphonio-methyl[6]helicene and D-(—)-dibenzoyltartaric acid was successful, as was the separation of [6]helicene on polymers . 

We became interested in synthesizing both the enantiomers of differolide to clarify whether one or both of them are bioactive. Our synthesis is summarized in Figure 5.14 and 5.15.23 Because both the enantiomers 135 and 135 were necessary for bioassay, we adopted enantiomer separation (optical resolution) of an intermediate as our key step (Figure 5.14). A crystalline acetal (-)-B was obtained from ( )-A and (—)-menthol, and analysed by X-ray to reveal its structure as (—)-B, basing on the known absolute configuration of (-)-menthol. When (+)-menthol was used for acetal formation, crystalline (+)-B was obtained in a similar manner. We thus secured both (-)-B and (-t-)-B as pure crystals. 

An interesting synthesis of a 17-phosphasteroid system is based on the Diels-Alder reaction of the optically active benzyl phenyl Pw7.i-(2-methoxycarbonylethenyl)phosphine oxide (30) which adds to 1-vinylnaphthalene (31) regioselectively, albeit with low diastereoselectivity 70% d.r. [(17 .2/J)/(1S,2,S)] 65 35). The major 32 and the minor 33 adduct are separated by fractional crystallization and separately converted into the 17-phosphasteroid system 34 and its enantiomer 35, respectively12. 

A surprisingly different approach was followed for obtaining both enantiomers of l,2-bis(di-phenylphosphino)cyclopentane 26. a ligand used in catalytic hydrogenations (Section D.2.5.1.2.1.1.) and hydrosilylation (Section D.9.). The racemic product was prepared by the reaction of cyclopentene with white phosphorus and phosphorus trichloride at elevated temperatures, followed by treatment with phenylmagnesium bromide. The racemate formed a complex with nickel(II) bromide which undergoes a Pasteur-type spontaneous resolution on crystallization from dichloromethane. The crystals were separated by hand27. 

The product will have one enantiomer In excess [say, (AR) > (AS)]. When this product Is recrystalllzed from solution there are several pathways open to It the two enantiomers may crystallize In separate, chiral crystals (spontaneous resolution). These crystals cannot be of stack structures because of the bulkiness of the substituents nor can they be of pair structures, since In any one crystal all the molecules are homochlral, so that the symmetry elements of the crystal cannot Include a center of Inversion. The crystal structure must be such that adjacent parallel molecules are poorly overlapped (the stack axis sharply tilted with respect to the mean molecular plane). Crystals of this so-called Y typs structure are known to show monomer emission and. In general, to be nonphotodlmerlzlng. 

Table 3.3-8 Results of enantiomer separation using the method of inclusion crystallization by suspension.

Scheme 7. Examples for Enantiomer Separations by Crystallization with TADDOLs. Besides the original TADDOL (from tartrate acetonide and PhMgX), Toda et al. [44] have often used the cyclopentanone- and cyclohexanone-derived analogs. The dynamic resolution (resolution with in-situ recychng) of 2-(2-methoxyethyl)cyclohexanone was reported by Tsunoda et al. The resolved compounds shown here are only a small selection from a large number of successful resolutions, which include alcohols, ethers, oxiranes, ketones, esters, lactones, anhydrides, imides, amines, aziridines, cyanohydrins, and sulfoxides. The yields given refer to the amount of guest compound isolated in the procedure given. Since we are not dealing with reactions (for which we use % es to indicate enantioselectivity with which the major enantiomer is formed), we use % ep (enantiomeric purity of the enantiomer isolated from the inclusion...

In order to prevent spontaneous crystallization of the other isomers, processes to remove concentration (supersaturation) of the other isomers are essential. In general this has been done by crystallization of the undesired enantiomer in parallel or in series with the crystallization of the desired enantiomer. Figure 13 (9) illustrates some parallel processes where undesired enantiomers are crystallized either in a separate crystallizer where mother liquors circulate or in a single crystallizer with separated space. The obtained undesired enantiomer is then converted into the desired enantiomer by the racemization reaction to improve the yield of the desired component. Our proposal is to combine the preferential crystallization of the desired isomer with the racemization reaction in a single crystallization vessel (10), The idea is not new and is outlined in a book by Jacques et al. where the use of aldehyde or ketone as the catalyst for the racemization reaction is suggested. 

So far we have left unanswered an important question about optically active compounds and racemic forms How are enantiomers separated Enantiomers have identical solubilities in ordinary solvents, and they have identical boiling points. Consequently, the conventional methods for separating organic compounds, such as crystallization and distillation, fail when applied to a racemic form. 

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